Positron emission tomographic (PET) imaging of the living human brain serotonin transporter (SERT) depends upon the development of high specific activity radiotracers that display high affinity and selectivity for the SERT sites and low nonspecific binding. The proposed research is focused on the design, synthesis, in vitro pharmacological characterization, and in vivo imaging in nonhuman primates of fluorine-18 (18F) labeled ligands, for the potential in vivo imaging of the SERT in patients with neuropsychiatric and drug addiction disorders. The research involves three phases: (1) the development of synthetic methods for the preparation of novel 18F labeled analogues of N,N-dimethyl-2-(2'-amino-4'- hydroxymethylphenylthio)benzylamine (HOMADAM), (2) the in vitro determination of relative affinities of fluorine-19 containing candidates in transfected cells stably expressing the human dopamine transporter (DAT), norepinephrine transporter (NET), or SERT, and (3) microPET studies defining time-activity curves (TAC) for specific and nonspecific binding in brain regions of interest (ROI) in cynomolgus monkeys. PUBLIC HEALTH RELEVANCE: Drug addiction and neuropsychiatric diseases have hit millions of Americans. The outcome of the K01 proposal will help us understand the mechanisms responsible for those diseases as well as develop more effective treatments to improve public health and quality of life.